Thiazolidinediones and the fracture risk
Case-control studies of patients with fractures have found that subjects with diabetes have at least a twofold higher risk of fracture than subjects without diabetes, with an increased risk of hip, humerus, and foot fractures in elderly diabetic subjects. Risk factors that contribute to increased fracture in diabetic subjects include number of falls, insulin use, functional disability, diabetes duration, and poor vision. In addition, lower bone strength (BMD) might be expected to increase risk for the development of osteoporosis and fracture.
Towards elucidation of the central nervous system network involved in leptin control of bone formation
Once it was known that leptin acts on the central nervous system, the next step was to identify leptin-sensitive neurons controlling bone formation. This was achieved through chemical lesioning in wild-type and leptin signaling-deficient mice, and the use of other genetically modified mouse models. These experiments established that hypothalamic neural networks regulate bone formation. The final proof that leptin was the mediator came when ob/ob mice, which lack leptin, with destroyed arcuate or ventromedial hypothalamic (VMH) neurons received leptin ICV (intracerebroventricular) infusion. In this situation, leptin ICV infusion decreased body weight but did not affect bone formation parameters or bone mass. Thus, VMH neurons regulate bone formation under the control of leptin [1, 2].
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Leptin: in search of a hormonal regulation of bone formation
Two major features of osteoporosis are that osteoporosis invariably follows gonadal failure, and that obesity protects from it. These two observations suggest the existence of a common regulation of body weight (or appetite), reproduction, and bone mass. Since appetite and reproduction are governed by the hypothalamus, this hypothesis implies that the control of bone remodeling may also, in part, originate from the hypothalamus.
Strong association between femoral neck BMD and vertebral fracture incidence during treatment with strontium ranelate
Bone mineral density (BMD) measurements are used to diagnose osteoporosis and to follow the patients under antiosteoporotic treatment. Several randomized, controlled trials have demonstrated that pharmacological agents increase BMD and reduce the risk of fracture. However the value of this increase in BMD differs widely while reductions in vertebral fracture risks are comparable. For antiresorptive agents, the predictive value of BMD changes for fracture risk reduction is highly controversial, relationship between changes in BMD and fracture risk being very low.
Inflammation markers are predictive of fractures
The inflammation of aging hypothesis purports that aging is the accumulation of damage, which results, in part, from chronic activation of the inflammatory process. This process is believed to play an important role in deterioration of the cardiovascular system and skeleton. Cytokines play major roles in regulating bone remodeling in the bone microenvironment, but their relationship to fractures is uncertain.
 Download here the slide set presented by Prof. Friedlander, on Thursday, March 29th. |
